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CaMKII induces permeability transition through Drp1 phosphorylation during chronic β-AR stimulation

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  • Shangcheng Xu

    (Mitochondria and Metabolism Center, University of Washington
    Third Military Medical University)

  • Pei Wang

    (Mitochondria and Metabolism Center, University of Washington)

  • Huiliang Zhang

    (Mitochondria and Metabolism Center, University of Washington)

  • Guohua Gong

    (Mitochondria and Metabolism Center, University of Washington)

  • Nicolas Gutierrez Cortes

    (Mitochondria and Metabolism Center, University of Washington)

  • Weizhong Zhu

    (Nantong University School of Pharmacy)

  • Yisang Yoon

    (Georgia Regents University)

  • Rong Tian

    (Mitochondria and Metabolism Center, University of Washington)

  • Wang Wang

    (Mitochondria and Metabolism Center, University of Washington)

Abstract

Mitochondrial permeability transition pore (mPTP) is involved in cardiac dysfunction during chronic β-adrenergic receptor (β-AR) stimulation. The mechanism by which chronic β-AR stimulation leads to mPTP openings is elusive. Here, we show that chronic administration of isoproterenol (ISO) persistently increases the frequency of mPTP openings followed by mitochondrial damage and cardiac dysfunction. Mechanistically, this effect is mediated by phosphorylation of mitochondrial fission protein, dynamin-related protein 1 (Drp1), by Ca2+/calmodulin-dependent kinase II (CaMKII) at a serine 616 (S616) site. Mutating this phosphorylation site or inhibiting Drp1 activity blocks CaMKII- or ISO-induced mPTP opening and myocyte death in vitro and rescues heart hypertrophy in vivo. In human failing hearts, Drp1 phosphorylation at S616 is increased. These results uncover a pathway downstream of chronic β-AR stimulation that links CaMKII, Drp1 and mPTP to bridge cytosolic stress signal with mitochondrial dysfunction in the heart.

Suggested Citation

  • Shangcheng Xu & Pei Wang & Huiliang Zhang & Guohua Gong & Nicolas Gutierrez Cortes & Weizhong Zhu & Yisang Yoon & Rong Tian & Wang Wang, 2016. "CaMKII induces permeability transition through Drp1 phosphorylation during chronic β-AR stimulation," Nature Communications, Nature, vol. 7(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13189
    DOI: 10.1038/ncomms13189
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    Cited by:

    1. Xueqiang Wang & Xing Zhang & Ke Cao & Mengqi Zeng & Xuyang Fu & Adi Zheng & Feng Zhang & Feng Gao & Xuan Zou & Hao Li & Min Li & Weiqiang Lv & Jie Xu & Jiangang Long & Weijin Zang & Jinghai Chen & Fen, 2022. "Cardiac disruption of SDHAF4-mediated mitochondrial complex II assembly promotes dilated cardiomyopathy," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Jenny Zhe Liao & Hyung-lok Chung & Claire Shih & Kenneth Kin Lam Wong & Debdeep Dutta & Zelha Nil & Catherine Grace Burns & Oguz Kanca & Ye-Jin Park & Zhongyuan Zuo & Paul C. Marcogliese & Katherine S, 2024. "Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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